2. Academic Validation
  3. Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers

  • Mol Cancer Ther. 2021 Jun;20(6):999-1008. doi: 10.1158/1535-7163.MCT-21-0077.
Ahmed Hamed Salem 1 2,  Zhi-Fu Tao 1,  Orlando F Bueno 1,  Jie Chen 1,  Shuang Chen 1,  Rohinton Edalji 1,  Steven W Elmore 1,  Keith M Fournier 1,  Kaid C Harper 1,  Richard Hong 1,  Gary J Jenkins 1,  Jianguo Ji 1,  Russell A Judge 1,  John C Kalvass 1,  Russell C Klix 1,  Yi-Yin Ku 1,  Joel D Leverson 1,  Richard A Marks 1,  Kennan C Marsh 1,  Rajeev M Menon 1,  Chang H Park 1,  Darren C Phillips 1,  Yu-Ming Pu 1,  Saul H Rosenberg 1,  Yeshwant D Sanzgiri 1,  Ahmad Y Sheikh 1,  Yi Shi 1,  Deanne Stolarik 1,  Ahmed A Suleiman 3,  Xilu Wang 1,  Geoff G Z Zhang 1,  Nathaniel D Catron 1,  Andrew J Souers 4
Affiliations

Affiliations

  • 1 AbbVie, Inc., North Chicago, Illinois.
  • 2 Ain Shams University, Cairo, Egypt.
  • 3 AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.
  • 4 AbbVie, Inc., North Chicago, Illinois. Andrew.souers@abbvie.com.
PMID: 33785651 DOI: 10.1158/1535-7163.MCT-21-0077
Abstract

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the Bcl-2 Inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within Bcl-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

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